1-228157866-C-G

Variant names:

• chr1-228157866-C-G
• rs75469429
• NM_020435.4:c.108C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_020435.4(GJC2):​c.108C>G​(p.Ile36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I36I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJC2 NM_020435.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.49
• Publications: 5 publications found

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

GJC2 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• lymphatic malformation 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary spastic paraplegia 44

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020435.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.8719 (below the threshold of 3.09). Trascript score misZ: -1.3976 (below the threshold of 3.09). GenCC associations: The gene is linked to hypomyelinating leukodystrophy 2, hereditary spastic paraplegia 44, lymphatic malformation 3, lymphatic malformation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 1-228157866-C-G is Pathogenic according to our data. Variant chr1-228157866-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2078.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020435.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	NM_020435.4	MANE Select	c.108C>G	p.Ile36Met	missense	Exon 2 of 2	NP_065168.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	ENST00000366714.3	TSL:1 MANE Select	c.108C>G	p.Ile36Met	missense	Exon 2 of 2	ENSP00000355675.2
	GJC2	ENST00000886860.1		c.108C>G	p.Ile36Met	missense	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.108C>G	p.Ile36Met	missense	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary spastic paraplegia 44 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		-1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.89		Gain of catalytic residue at V32 (P = 0.0435)
MVP		0.93
ClinPred		0.97	D
GERP RS		-6.3
Varity_R		0.76
gMVP		0.90
Mutation Taster		=71/29	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75469429; hg19: chr1-228345567;